Lassa virus and Ebola virus are two of the mostdevastatinghumanpathogensandinfectionwithbothcan lead to severe hemorrhagic fever with case fatality rates in excess of 70%. It is estimated that tens of thousandsofpeoplediefromLassafevereachyear.DespitethehighcasefatalityratesofhospitalizedEbola and Lassa fever patients, it is wellestablishedthatasymptomaticormildlysymptomaticinfectionsoccurin both Lassa fever and Ebola. We know that virus genetics play key roles in determining disease severity, however, mechanistic insights are lacking and no systematic studies have been performed toidentifyvirus correlates ofhumandisease.Similarly,ahighproportionofLassafeverandEbolasurvivorsdevelopserious long-termsymptomsassociatedwiththeirdisease,butvirusfactorsthatmaydeterminethesecomplications remain elusive. The central hypothesis of this project, is that speci?c genetic factors in Lassa and Ebola viruses critically in?uence infection outcomes. Working directly with unique Lassa and Ebolapatientandsurvivorcohortsin WestAfrica,wewillidentifyLassavirusandEbolavirusfactorsthataredeterminantsofhumandisease.We will integrate high-throughput ?omics? approaches, high-containment experimentation, and computational modelingtoelucidatemolecularnetworksthatdetermineinfectiousdiseaseseverity.Basedonthese?ndings, wewillbuildpredictivemodelsthatcanbeusedtodetermineriskfromLassavirusandEbolavirusinfection. We will achieve these goals by completing three overarching goals. In Speci?c Aim 1, we will create and analyzelarge-scalegenomicdatasetsofLassaandEbolaviruses,andgenotypeofinfectedpatients.Wewill performdeepinvestigationsofhowthevirusesevolveastheytransmitfromtheirnaturalreservoirstohumans and between humans, and determine how that can a?ect clinical outcomes. In Speci?c Aim 2, we will functionally characterize, in a high-throughput manner, individual Lassa virus and Ebola virus mutations hypothesizedtoin?uenceinfectiousoutcomes.Finally,inSpeci?cAim3wewillperformexperimentsinhigh containment to determine functional e?ects of individual mutations in Lassa virus and Ebola virus, and investigatemechanismsofimmuneescapeandinfection.Aspartofthisaim,wewillalsoengineerantibodies to better target both viruses, which can be used as a starting point for future therapeutics.